DESCRIPTION: Nicotinic cholinergic signaling plays key roles in the mammalian nervous system. Nicotinic acetylcholine receptors mediate excitatory signaling between neurons as post-synaptic receptors and, from extrasynaptic sites, modulate neurotransmitter release at diverse synapse types across virtually every area of the brain and spinal cord. Alterations in nicotinic cholinergic signaling are associated with a number of debilitating neurological disorders including Alzheimer's disease, schizophrenia and certain forms of epilepsy. Moreover, nicotine binding to nicotinic receptors in the nervous system initiates the cellular and molecular cascade that results in nicotine addiction. Despite the clear importance of nicotinic signaling in normal brain physiology and neuronal dysfunction, there are major gaps in our understanding of the molecular mechanisms by which nicotinic signaling is achieved, and the regulatory pathways that impact cholinergic signaling in the nervous system remain poorly defined. This proposal employs a highly tractable model system, the nematode C. elegans, to investigate the molecular details of cholinergic signaling in a defined nervous system. Our preliminary data show that nicotinic receptors play key roles in regulating the excitability of motor neurons in a well-characterized C. elegans motor circuit. In Aim 1, we will test the hypothesis that the expression and localization of specific receptor types are restricted to subsets of motor neurons, determine the molecular nature of pathways important for proper localization of nicotinic receptors on neurons, and test the roles of specific receptor types in the control of C. elegans behavior. In Aim 2, we will use patch clamp electrophysiology to directly measure cholinergic currents from motor neurons and assess the roles of these receptors in motor neuron physiology. In Aim 3, we will use a powerful genetic approach to uncover components of novel molecular pathways that regulate cholinergic signaling onto neurons. We expect that our studies will provide fundamental insights into the mechanisms of nicotinic receptor function in the central nervous system. Additionally, the identification and functional characterization of genetic pathways that regulate synapse formation and function in our experiments will ultimately yield novel drug targets for therapeutic strategies designed to treat neurological disorders involving cholinergic signaling. PUBLIC HEALTH RELEVANCE: Cellular communication in the nervous system requires the neurotransmitter acetylcholine and alterations in acetylcholine-mediated signaling are a hallmark of a wide variety of degenerative neurological disorders and nicotine addiction, yet we know very little about the molecular pathways that regulate this process in the nervous system. This proposal will explore the mechanisms by which acetylcholine transmits information between cells of the nervous system and uncover new genes required in this process. Our work will provide fundamental insights into the mechanisms of acetylcholine-mediated signaling and is expected to lead to the development of new therapies for the treatment of disorders arising from deficits in this process.